TRIGR - Primary Prevention Study for Type 1 Diabetes in Children at Risk

Diabetes Mellitus, Type 1 Clinical Trial

— TRIGR  

Official title:

TRIGR - Trial to Reduce IDDM in the Genetically at Risk

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00179777
• Other study ID #: MCT-49395
• Secondary ID: U01HD040364U01HD
• Status: Completed
• Phase: N/A
• Start date: May 6, 2002
• Est. completion date: September 30, 2017

Study information

• Verified date: July 2021
• Source: University of Helsinki
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) is an international effort to conduct a primary prevention nutrition trial for type 1 (insulin-dependent) diabetes. The TRIGR study was targeted at newborns who are at genetic risk for type 1 diabetes because their mother, father and/or full sibling has type 1 diabetes. All families were encouraged to breast feed their infants for as long as possible. Prior to birth, the child was randomly assigned to receive one of two infant formulas, should formula be required prior to 8 months of age. The study determined whether weaning to a possibly protective infant formula decreases these children's chances of developing diabetes - as it does in the animal models for diabetes.

Description:

The hypothesis for this study is that weaning to an extensively hydrolyzed infant formula will decrease the incidence of type 1 diabetes in subjects with risk-associated HLA genotypes and a first degree relative with type 1 diabetes, as it does in all relevant animal models for the disease.

Specific Aims:

I.a: To determine if weaning to a casein hydrolysate infant formula reduces the frequency of diabetes-predictive auto-antibodies in subjects with risk-associated HLA genotype and a first degree relative with type 1 diabetes (mother, father and/or full sibling).

I-b: To determine if weaning to a casein hydrolysate infant formula reduces the frequency of clinical diabetes in subjects with risk-associated HLA genotype and an affected first degree relative.

A secondary aim is to determine relationships between cow's milk antibodies, a measure of cow's milk exposure, and diabetes-associated auto-antibodies.

The mother of the unborn child is recruited during pregnancy. Randomization to one of two infant formulas takes place before birth (after 35 weeks gestation) or immediately after birth.

Experimental Arm: Use of extensively hydrolysed cow's milk based infant formula when needed in supplementation or substitution for breast milk through 6-8 months from birth.

Control Arm: Use of non-hydrolysed cow's milk based infant formula when needed in supplementation or substitution for breast milk through 6-8 months from birth.

All families were encouraged to breast feed their infants for as long as possible. The study infant formula was only used if exclusive breast feeding ceases before 8 months of age.

Cord blood for genotyping was obtained at birth, or failing that from a heel prick by 7 days of age. Only subjects with genotypes indicating increased genetic risk for type 1 diabetes remained in the intervention trial. All other subjects were withdrawn from the study.

All subjects were followed until the youngest subject turns age 10 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5156
• Est. completion date: September 30, 2017
• Est. primary completion date: March 31, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 7 Days

Eligibility

Inclusion Criteria:

• Biological parent and/or full (not half) sibling of the newborn infant had type 1 diabetes as defined by the World Health Organization

• The infant's parent or legal guardians gave signed consent to participate

Exclusion Criteria:

• An older sibling of the newborn infant had been included in the TRIGR intervention

• Multiple gestation

• The parents were unwilling or unable to feed the infant cow's milk based products for any reason (e.g., religious, cultural).

• The newborn infant had a recognizable severe illness such as those due to chromosomal abnormality, congenital malformation, respiratory failure needing assisted ventilation, enzyme deficiencies, etc.

• The gestational age of the newborn infant was less than 35 weeks.

• The infant was older than 7 days at randomization.

• Inability of the family to take part in the study (e.g. the family has no access to any of the Study Centers, the family has no telephone).

• The infant had received any infant formula other than Nutramigen prior to randomization.

• No HLA sample drawn before the age of 8 days.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

Dietary Supplement:
• Hydrolysed infant formula
Participants in the Hydrolysed infant formula -group received the test formula, casein hydrolysate (Nutramigen™, Mead Johnson Nutritionals), not containing antigenic CM protein, whenever breast milk is not available.
• Nonhydrolysed infant formula
Participants in the Nonydrolysed infant formula -group received the CM protein containing control formula which has an addition (20 %) of Nutramigen, whenever breast milk is not available.

Locations

Country	Name	City	State
Australia	Children's Hospital at Westmead	Westmead	New South Wales
Canada	Robarts Research Institute	London	Ontario
Czechia	3rd Faculty of Medicine, Charles University, University Hospital Vinohrady	Prague
Estonia	Tartu University Children's Hospital	Tartu
Finland	University of Helsinki	Helsinki
Germany	Kinderkrankenhaus auf der Bult	Hannover
Hungary	Semmelweis Medical University	Budapest
Italy	St. Michele Hospital	Cagliari	Sardinia
Italy	University Campus Bio-Medico of Rome	Rome
Luxembourg	Centre Hospitalier de Luxembourg	Luxembourg
Netherlands	Sophia Children's Hospital	Rotterdam
Poland	Medical University of Wroclaw	Wroclaw
Spain	Hospital de Cruces	Barakaldo	Vizcaya
Spain	Hospital Clinico San Carlos	Madrid
Sweden	University of Linkoping	Linkoping
Switzerland	University Children's Hospital	Zurich
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	The University of South Florida	Tampa	Florida

Sponsors (11)

Lead Sponsor	Collaborator
University of Helsinki	Academy of Finland, Canadian Institutes of Health Research (CIHR), Diabetes Research Foundation, Finland, Dutch Diabetes Research Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), European Community (EC), European Foundation for the Study of Diabetes, Juvenile Diabetes Research Foundation, Mead Johnson Nutrition, US Congress

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Czechia,  Estonia,  Finland,  Germany,  Hungary,  Italy,  Luxembourg,  Netherlands,  Poland,  Spain,  Sweden,  Switzerland, 

References & Publications (4)

Åkerblom HK, Knip M, Becker D, Dosch H-M, Dupré J, Ilonen J, Krischer JP and the TRIGR Study Group. The TRIGR Trial: Testing the Potential Link between Weaning Diet and Type 1 Diabetes. Immun, Endoc, Metab Agents in Med Chem 7:251-263, 2007.

Akerblom HK, Virtanen SM, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hämäläinen AM, Paronen J, Riikjärv MA, Ormisson A, Ludvigsson J, Dosch HM, Hakulinen T, Knip M; National TRIGR Study Groups. Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study. Diabetologia. 2005 May;48(5):829-37. Epub 2005 Apr 19. Erratum in: Diabetologia. 2005 Aug;48(8):1676. Riikjärv, MA [added]; Ormisson, A [added]; Ludvigsson, J [added]; Dosch, HM [added]; Hakulinen, T [added]; Knip, M [added]. — View Citation

TRIGR Study Group. Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Pediatr Diabetes. 2007 Jun;8(3):117-37. — View Citation

Writing Group for the TRIGR Study Group, Knip M, Åkerblom HK, Al Taji E, Becker D, Bruining J, Castano L, Danne T, de Beaufort C, Dosch HM, Dupre J, Fraser WD, Howard N, Ilonen J, Konrad D, Kordonouri O, Krischer JP, Lawson ML, Ludvigsson J, Madacsy L, Ma — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Type 1 Diabetes Mellitus	Number of participants with Type 1 diabetes mellitus assessed by (1) blood glucose and HbA1c at 12 and 18 months of age, and annually from age 2 to 10 years, and (2) oral glucose tolerance test at 6 and 10 years of age and in the final year of the study.	12 and 18 months and annually from 2 years up to 14 years
Secondary	Number of Participants With Diabetes Associated Autoantibodies	Diabetes associated autoantibodies (ICA, IAA, GADA, IA-2A) at 3, 6, 9, 12, and 18 months of age, and annually from age 2 to 10-14 years	3, 6, 9, 12, 18 months and annually from 2 years up to 14 years

External Links

•   TRIGR International website - Click here for more information on this study - www.TRIGR.org
•   TRIGR North America website - Click here for more information on this study - www.trigrnorthamerica.org